Sterile composition comprising a chelate complex for magnetic resonance imaging

ABSTRACT

A diagnostic medium contains at least one physiologically well tolerated complex salt comprising an anion of a complexing acid and one or more central ion or ions of an element with an atomic number of 21 to 29, 42, 44 or 57 to 83 and, optionally, one or more physiologically biocompatible cation or cations of an inorganic and/or organic base or amino acid, optionally, with additives customary in galenic formulations, dissolved or suspended in an aqueous medium.

This application is a continuation of application Ser. No. 07/933,918filed Aug. 27, 1992, abandoned which is a continuation of Ser. No.07/020,992 filed Mar. 2, 1987, abandoned which is a continuation-in-partof Ser. No. 06/573,184 filed Jan. 23, 1984, U.S. Pat. No. 4,647,447which is a continuation-in-part of Ser. No. 06/401,594 filed Jul. 26,1982 abandoned.

BACKGROUND OF THE INVENTION

Complexes or their salts have long been used in medicine, for example,as aids in administering poorly soluble ions (e.g., iron) and asantidotes (in which calcium or zinc complexes are preferred).fordetoxification in cases of inadvertent bodily incorporation of heavymetals or their radio isotopes.

SUMMARY OF THE INVENTION

It is an object of this invention to provide complex salts for use invaluable diagnostic techniques.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

It has now been found that physiologically well tolerated complex saltsformed from the anion of a complexing acid and one or more central ionsof an element with an atomic number of 21 to 29, 42, 44 or 57 to 83 and,optionally, also fomred from one or more physiologically biocompatiblecations of an inorganic and/or organic base or amino acid, surprisinglyare suitable for producing diagnostic media which are suitable for usein NMR, X-ray and/or ultrasonic diagnosis.

Thus, these objects have been attained by providing, preferably, adiagnostic medium containing at least one physiologically well toleratedcomplex salt of the formulae I or II ##STR1## wherein, X is --COOY,--PO₃ HY or --CONHOY; Y is a hydrogen atom, a metal ion equivalentand/or a physiologically biocompatible cation of an inorganic or organicbase or amino acid, A is ##STR2## wherein X is defined as above, each R₁is hydrogen or methyl, R₂ and R₃ together represent a trimethylene groupor a tetramethylene group or individually are hydrogen atoms, loweralkyl groups (e.g., 1-8 carbon atoms), phenyl groups, benzyl groups, orR₂ is a hydrogen atom and R₃ is

    --(CH.sub.2).sub.p --C.sub.6 H.sub.4 --W-protein

wherein p is 0 or 1, W is --NN--, --NHCOCH₂ -- or --NHCS--, -proteinrepresents a protein residue, m is the number 1, 2 or 3, Z is an oxygenatom or a sulfur atom or the group ##STR3## wherein X is as definedabove and R₄ is a lower alkyl group (e.g., 1-8 carbon atoms), V has thesame meaning as X, or is

    --CH.sub.2 OH, --CONH(CH.sub.2).sub.n X, or --COB

wherein X is as defined above, B is a protein or lipid residue, n is anumber from 1 to 12, or if R₁, R₂ and R₃ are hydrogen atoms, both V'stogether are the group ##STR4## wherein X is as defined above, w is thenumber 1, 2 or 3, provided that at least two of the substituents Yrepresent metal ion equivalents of an element with an atomic number of21 to 29, 42, 44 or 57 to 83.

New such salts include complex salts of the formula ##STR5## wherein X,A, V and R₁ are as defined above provided they contain 3 to 12substituents Y, of which at least two are a metal ion equivalent of anelement with an atomic number of 21 to 29, 42, 44 or 57 to 83 and, inaddition, at least one substituent Y is the physiologicallybiocompatible cation of an organic base or amino acid, wherein theoptionally remaining substituents Y represent hydrogen atoms or cationsof an inorganic base.

A further aspect of the invention is a media for improvement of theimage quality of proton nuclear spin tomography and X-ray diagnosiscontaining at least one paramagnetic physiologically compatible complexsalt of a macrocyclic compound of formula VII ##STR6## in which R⁹, ineach case, is a hydrogen atom, a hydrocarbon radical or a carboxymethylradical or the two radicals R⁹ together form a group of general formulaVIIa ##STR7## A, in each case, represents a hydrocarbon radical, X, ineach case, represents a nitrogen atom or phosphorus atom,

D, in each case, represents an oxygen atom or sulfur atom, a group offormula ##STR8## (with R being hydrogen, carboxymethyl or a hydrocarbonradical) or a hydrocarbon radical, provided that at least two of thegroups or atoms, for which D stands, are oxygen atoms, sulfur atoms or agroup of the formula ##STR9## and s, t and v are whole numbers from 0 to5, and

of the ions of lanthanide elements of atomic numbers 57 to 70 or theions of transition metals of the atomic numbers 21 to 29, 42 and 44, and

optionally of an inorganic or organic acid.

If A and D in formula VII stand for hydrocarbon radicals, there arepreferably straight-chain or branched alkylene or alkenylene radicalswith 2 to 8 carbon atoms such as ethylene, propylene, butylene andhexylene and their unsaturated analogs, further cycloalkylene andcycloalkenylene radicals such as cyclopropylene, cyclobutylene,cyclohexylene and cycloheptylene and their unstaturated analogs as wellas aromatic radicals such as phenylene.

The hydrocarbon radicals indicated by R⁹ are preferably straight-chainor branched alkyl or alkenyl radicals with 1 to 8 carbon atoms, furthercycloalkyl, aralkyl and aryl radicals with 3 to 12 carbon atoms.Suitable complexing agents are, for example, 5,6-benzo-4,7,13,16,21,24-hexaoxa -1,10-diazabicyclo[8.8.8]hexacosane,1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane,1,4,8,12-tetraazacyclopentadecane and 1,4,8,11-tetraazacyclotetradecaneand 1,4,8,11-tetraazacyclotetradecane -N,N',N", N'"-tetraacetic acid.

DETAILED DISCUSSION

The element of the above-mentioned atomic number which forms the centralion or ions of the physiologically well tolerated complex salt,obviously must not be radioactive for the intended use of the diagnosticmedium according to this invention.

If the medium according to the invention is intended to be used in NMRdiagnosis (see, e.g., European patent application 71 564 as well asparent Ser. No. 401,594, both of which are entirely incorporated byreference herein), the central ion of the complex salt must beparamagnetic. It preferably is the divalent or trivalent ions ofelements with an atomic number of 21 to 29, 42, 44 and 58 to 70.Suitable ions, for example, include chromium(III), manganese(II),iron(III), iron(II), cobalt(II), nickel(II), copper(II),praseodymium(III), neodymium(III), samarium(III) and ytterbium(III).Because of their very strong magnetic moments, gadolinium(III),terbium(III), dysprosium(III), holmium(III), and erbium(III) arepreferred.

If the medium according to the invention is intended for use in X-raydiagnosis, the central ion has to be derived from an element with ahigher atomic number to achieve a sufficient absorption of X-rays. Ithas been found that diagnostic media containing a physiologically welltolerated complex salt with central ions of elements with atomic numbersof 57 to 83 are suitable for this purpose. These include, for example,lanthanum(III), the above mentioned ions of the lanthanide group,gold(III), lead(II) or, especially, bismuth(III).

All of the media according to the invention, also intended for use bothin NMR and X-ray diagnosis, are also suitable for use in ultrasonicdiagnosis.

By "complexing acid" herein is meant an acid which acts as a ligand forthe metals of interest thereby forming a chelate therewith.

Suitable complexing acids include those which are customarily used forcomplexing of the above mentioned central ions. These include, forexample, those containing 3 to 12, preferably 3 to 8, methylenephosphonic acid groups, methylene carbohydroxamic acid groups,carboxyethylidene groups, or especially carboxymethylene groups, one,two or three of which are bonded to a nitrogen atom supporting thecomplexing. If three of the acid groups are bonded to a nitrogen atom,then the underlying acids complexing the complex salts of formula II arepresent. If only one or two of the acid groups are bonded to a nitrogenatom, that nitrogen is bonded to another nitrogen atom by an optionallysubstituted ethylene group or by up to four separate ethylene unitsseparated by a nitrogen or oxygen or sulfur atom supporting thecomplexing. Complexing acids of this type are preferably those offormula I.

The complexing acids can be coupled as conjugates with biomolecules thatare known to concentrate in the organ or part of the organ to beexamined. These biomolecules include, for example, hormones such asinsulin, prostaglandins, steroid hormones, amino sugars, peptides,proteins, lipids etc. Conjugates with albumins, such as human serumalbumin, antibodies, for example, monoclonal antibodies specific totumor associated antigens, or antimyosin etc. are especially notable.The diagnostic media formed therefrom are suitable, for example, for usein tumor and infarct diagnosis. Conjugates with liposomes, or byinclusion of the salts in liposomes, in both cases which, for example,are used as unilamellar or multilamellar phosphatidylcholine-cholesterolvesicles, are suitable for liver examinations. Conjugating can beconventionally effected either via a carboxyl group of the complexingacid or, in the case of proteins or peptides, also by a (CH₂)_(p) --C₆H₄ --W-- group, as defined for R₃ above. Several acid radicals can bepartially bonded to the macro-molecular biomolecule in the conjugationof the complex salts with proteins, peptides or lipids. In this case,each complexing acid radical can carry a central ion. If the complexingacids are not bonded to biomolecules, they optionally carry two centralions, usually and especially one central ion.

Suitable complex salts of formula I include, for example, those offormula Ia ##STR10## where X, V, R₁, R₂ and R₃ are as defined above.

The following complexing acids, among others, are suitable forproduction of the complex salts of formula Ia:ethylenediaminetetraacetic acid, ethylenediamine-tetraacethydroxamicacid, trans-1, 2-cyclohexenediamine-tetraacetic acid,dl-2,3-butylenediamine tetraacetic acid,dl-1,2-butylenediaminetetraacetic acid, dl-1,2-diaminepropanetetraaceticacid, 1,2-diphenylethylene-diaminetetraacetic acid,ethylenedinitrilotetrakis(methane phosphonic acid) andN-(2-hydroxyethyl)-ethylenediamine-triacetic acid.

Other suitable complex salts of formula I include, for example, those offormula Ib ##STR11## where X, V, Z, R₁ and m are as defined above. If Zis an oxygen atom or a sulfur atom, complex salts with m equal to 1 or2are preferred.

The following complexing acids, among others, are suitable forproduction of the complex salts of formula Ib:diethylenetriaminepentaacetic acid, triethylene-tetraaminehexaaceticacid, tetraethylenepentaaminehepta-acetic acid, 13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriacontanedioic acid,3,9-bis-(1-carboxyethyl)-3,6,9-triazaundecanedioic acid,diethylenetriaminepentakis-(methylene phosphonic acid),1,10-diaza-4,7-dioxadecane-1,1-10,10-tetraacetic acid and,1,10-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid.

Moreover, suitable complex salts of formula I, include those of formulaIc ##STR12## where X and w are as defined above.

The following complexing acids, among others,-are suitable forproduction of the complex salts of formula Ic:1,4,8,11-tetraazacyclotetradecanetetraacetic acid and especially1,4,7,10-tetraazacyclododecanetetraacetic acid.

Other complexing acids, which are suitable for production of the complexsalts of formula I, include for example:1,2,3-tris-[bis-(carboxymethyl)-amino-]-propane andnitrilotris-(ethylenenitrilo)-hexaacetic acid. Ni-trilotriacetic acid isan example of a complexing acid suitable for production of the complexsalts of formula II.

If not all of the hydrogen atoms of the complexing acids are substitutedby the central ion or central ions, it is advantageous to increase thesolubility of the complex salt to substitute the remaining hydrogenatoms with physiologically biocompatible cations of inorganic and/ororganic bases or amino acids. For example, the lithium ion, thepotassium ion and especially the sodium ion are suitable inorganiccations. Suitable cations of organic bases include, among others, thoseof primary, secondary or tertiary amines, for example, ethanolamine,diethanolamine, morpholine, glucamine, N,N-dimethylglucamine orespecially N-methylglucamine. Lysines, arginines or ornithines aresuitable cations of amino acids, as generally are those of other basicnaturally occurring such acids.

All of the complexing acids used in the agents according to theinvention are known or can be produced in a way fully conventional inthe art. Thus, for example, production of13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriacontanedioicacid is produced in an improvement of the method proposed by R. A.Bulman et al. in Naturwissenschaften 68 (1981) 483, as follows:

17.85 g (=50 mmole) of 1,5-bis(2,6-dioxomorpholino)-3-azapentane-3-acetic acid is suspended in 400 ml of drydimethylformamide and heated for 6 hours to 70° C. after addition of20.13 g (=100 mmole) of 11-amino -undecanoic acid. The clear solution isconcentrated in vacuo. The yellow oil residue is stirred with 500 ml ofwater at room temperature. In this way, a white, voluminous solidprecipitates which is suctioned off and washed several times with water.The resulting product is put into 200 ml of acetone for furtherpurification and stirred for 30 minutes at room temperature. Aftersuctioning off and drying in vacuo at 50° C., 36.9 g (=97% of theory) ofa white powder with a melting point of 134°-138° C. is obtained.

Conjugation of the complexing acids with biomolecules also occurs bymethods fully conventional in the art, for example, by reaction ofnucleophilic groups of bio-molecules, for example, amino, hydroxy, thioor imidazole groups with an activated derivative of the complexing acid.For example, acid chlorides, acid anhydrides, activated esters, nitrenesor isothiocyanates can be used as activated derivatives of complexingacids. On the other hand, it is also possible conventionally to react anactivated biomolecule with the complexing acid. Substituents of thestructure --C₆ H₄ N₂ + or C₆ H₄ NHCOCH₂ -- halogen can also be used forconjugating with proteins.

Production of the complex salts is also known or can be performed fullyconventionally as known in the art, e.g., in processes in which themetal oxide or a metal salt (for example, nitrate, chloride or sulfate)of an element with an atomic number of 21to 29, 42, 44 or 57 to 83 isdissolved or suspended in water and/or a lower alcohol (such as methyl,ethyl or isopropyl alcohol) and added to a solution or suspension of theequivalent amount of the complexing acid in water and/or a lower alcoholand stirred, if necessary, with heating moderately or to the boilingpoint, until the reaction is completed. If the complex salt that isformed is insoluble in the solvent that is used, it is isolated byfiltering. If it is soluble, it can be isolated by evaporation of thesolvent to dryness, for example, by spray drying.

If acid groups are still present in the resulting complex salt, it isoften advantageous to convert the acidic complex salt into a neutralcomplex salt by reaction with inorganic and/or organic bases or aminoacids, which form physiologically biocompatible cations, and isolatethem. In many cases, the procedure is even unavoidable since thedissociation of the complex salt is moved toward neutrality to such anextent by a shift in the pH value during the preparation that only inthis way is the isolation of homogeneous products or at least theirpurification made possible. Production is advantageously performed withorganic bases or basic amino acids. It can also be advantageous,however, to perform the neutralization by means of inorganic bases(hydroxides, carbonates or bicarbonates) of sodium, potassium orlithium.

To produce the neutral salts, enough of the desired base can be added tothe acid complex salts in an aqueous solution or suspension that thepoint of neutrality is reached. The resulting solution can then beconcentrated to dryness in vacuo. It is often advantageous toprecipitate the neutral salts by addition of solvents miscible withwater, for example, lower alcohols (methyl, ethyl, isopropyl alcohols,etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc.) and thus obtain crystallizates thatisolate easily and purify well. It has been found. particularlyadvantageous to add the desired bases to the reaction mixture evenduring complexing and thus eliminate a process stage.

If the acid complex salts contain several free acid groups, it is thenoften advantageous to produce neutral mixed salts which contain bothinorganic and organic physiologically biocompatible cations ascounterions. This can be done, for example, by reacting the complexingacids in an aqueous suspension or solution with the oxide or salt of theelement supplying the central ion and less than the full amount of anorganic base necessary for neutralization, e.g., half, isolating thecomplex salt that is formed, purifying it, if desired, and then addingit to the amount of inorganic base necessary for completeneutralization. The sequence of adding the bases can also be reversed.

Production of the diagnostic media according to the invention is alsoperformed in a way known in the art. For example, the complex salts,optionally with addition of the additives customary in galenicals, aresuspended or dissolved in an aqueous medium and then the solution orsuspension is sterilized. Suitable additives include, for example,physiologically biocompatible buffers (as, for example, tromethaminehydrochloride), slight additions of complexing agents (as, for example,diethylenetriaminepentaacetic acid) or, if necessary, electrolytes (forexample, sodium chloride).

In principle, it is also possible to produce the diagnostic mediaaccording to the invention without isolating the complex salts. In thiscase, special care must be taken to perform the chelating so that thesalts and salt solutions according to the invention are essentially freeof uncomplexed, toxically active metal ions. This can be assured, forexample, using color indicators such as xylenol orange by controltitrations during the production process. The invention therefore alsorelates to the process for production of the complex compound and itssalts. A purification of the isolated complex salt can also be employedas a final safety measure.

If suspensions of the complex salts in water or physiological saltsolutions are desired for oral administration or other purposes, a smallamount of soluble complex salt is mixed with one or more of the inactiveingredients customary in galenicals and/or surfactants and/or aromaticsfor flavoring.

The diagnostic media according to this invention preferably contain 1μmole to 1 mole per liter of the complex salt and, as a rule, areadministered in doses of 0.001 to 5 mmole/kg. They are intended for oraland particularly parenteral administration.

The media according to the invention, meet the various requirements forsuitability as contrast media for nuclear spin tomography. They areexceptionally suitable for improving the image, e.g., itsexpressiveness, which is obtained with nuclear spin tomography byenhancement of the signal strength after oral or parenteral application.Moreover, they exhibit the great effectiveness that is necessary to loadthe body with the least possible amount of foreign substances whileachieving beneficial results, and the good tolerance that is necessaryto maintain the noninvasive character of the examination. (The compoundsmentioned, for example in J. Comput. Tomography 5,6:543-46 (1981), inRadiology 144, 343 (1982) and in Brevet Special de Medicament No. 484M(1960) are too toxic). The good aqueous solubility of the mediaaccording to the invention makes it possible to produce highlyconcentrated solutions and in this way to keep the volume load of thecirculatory system within supportable limits and compensate for dilutionby the body fluids, i.e., NMR diagnostic media must be 100 to 1000 timesmore soluble in water than for conventional NMR spectroscopy. Moreover,the media according to the invention exhibit not only a great stabilityin vitro but also an exceptionally great stability in vivo, so that arelease or exchange of the ions, which are not covalently bonded in thecomplexes and which in themselves would be toxic in the 24 hours inwhich--as pharmacological research has shown--the new contrast media aregenerally completely eliminated, occurs only extremely slowly. Forexample, the conjugates with proteins and antibodies used for tumordiagnosis, even in very low dosage, result in such a surprisingly greatenhancement of the signal that in this case solutions in correspondinglylow concentrations can be applied.

The media according to the invention are also exceptionally suitable asX-ray contrast media. In this case, it should be particularly stressedthat with them no indications of anaphylactic type reactions can bedetected as opposed to contrast media containing iodine which are knownin biochemical and pharmacological tests. These agents of this inventionare especially valuable because of the favorable absorption propertiesin the range of higher X-ray tube voltages for digital subtractiontechniques.

The media according to the invention are also suit able as ultrasonicdiagnostic media because of their property of favorably influencing theultrasonic rate.

In contrast to conventional X-ray diagnosis with radiopaque X-raycontrast media, in NMR diagnosis with paramagnetic contrast medium thereis no linear dependence of the signal enhancement on the concentrationused. As control tests show, an increase in the applied dosage does notnecessarily contribute to a signal enhancement, and with a high dosageof paramagnetic contrast medium the signal can even be obliterated. Forthis reason, it was surprising that some pathological processes can beseen only after application of a strongly paramagnetic contrast medium,according to the invention, higher than the doses indicated in EP 71564(which can be from 0.001 mmole/kg to 5 mmole/kg) Thus, for example, adefective blood-brain barrier in the region of a cranial abscess can bedetected only after a dose of 0.05-2.5 mmole/kg, preferably 0.1-0.5mmole/kg, of paramagnetic complex salts of this invention, for example,gadolinium diethylenetriaminepentaacetic acid ormanganese-1,2-cyclohexenediaminetetraacetic acid in the form of theirsalts that have good aqueous solubility. For a dose greater than 0.1mmole/kg, solutions of high concentrations up to 1 mole/l, preferably0.25 to 0.75 mole/l, are necessary, since only in this way is the volumeload reduced and handling of the injection solution assured.

Particularly low dosages (under 1 mg/kg) and thus lower concentratedsolutions (1 μmole/1 to 5 mmole/l), than indicated in EP 71564, can beused in this invention for organ-specific NMR diagnosis, for example,for detection of tumors and cardiac infarction.

Generally, the agents of this invention are administered in doses of0.001-5 mmole/kg, preferably 0.005-0.5 mmole/kg for NMR diagnostics; indoses of 0.1-5 mmole/kg, preferably 0.25-1 mmole/kg for X-raydiagnostics, e.g., analogous to meglumine-diatrizoate, and in doses of0.1-5 mmole/kg, preferably 0.25-1 mmole/kg for ultrasound diagnostics.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merley illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever. In the followingexamples, all temperatures are set forth uncorrected in degrees Celsius;unless otherwise indicated, all parts and percentages are by weight.

An especially preferred salt of this invention, inter alia, is that ofexample 5 (Production of the di-N-Methyl-glucamine salt ofgadolinium(III) complex of diethylene-triamine-N,N,N',N",N"-pentaaceticacid, C₂₈ H₅₄ GdN₅ O₂₀).

Preferred salts of formula I(c) are those of examples 11 and 18,especially example 18.

In the compounds involving formula IC, X can also be COB as defined forthe equivalent V group above. Thus, the salts can be attached tobiomolecules as generically described above.

EXAMPLE 1

Production of the gadolinium(III) complex of nitrilo-N,N,N-triaceticacid C₆ H₆ GdNO₆

The suspension of 36.2 g (=100 mmoles) of gadolinium (Gd₂ O₃) and 38.2 g(=200 mmoles) of nitrilotriacetic acid in 1.2 liters of water is heatedto 90° C. to 100° C. with stirring and is stirred at this temperaturefor 48 hours. Then the insoluble part is filtered off with activatedcarbon and the filtrate is evaporated to dryness. The amorphous residueis pulverized.

Yield: 60 g; (87% of theory) Melting point: 300° C.

The iron(III) complex of nitrilo-N,N,N-triacetic acid is obtained withthe aid of iron(III) chloride, FeCl₃.

EXAMPLE 2

Production of the disodium salt of gadolinium(III) complex of13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriacontanedioicacid, C₃₆ H₆₀ GdN₅ O₁₂.2 Na

15.2 g (=20 mmoles) of 13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriacontanedioic acid are suspended in 400ml of water and heated to 95° C. 7.43 g (=20 mmoles) of gadolinium(III)chloride hexahydrate, dissolved in 60 ml of water, are slowly added dropby drop. It is kept at this temperature for 2 hours and then mixed with60 ml of 1N sodium hydroxide solution to neutralize the resultinghydrocloric acid.

After complete reaction (tresting with xylenol orange), the resultingprecipitation is filtered and washed with water until free of chloride.17.60 g (96% of theory) of a white powder, insoluble in water, with amelting point of 290°-292° C. are obtained.

Gadolinium(III) complex of 13,23-dioxo-15,18,21-tris(carboxymethyl) -12,15, 18, 21, 24-pentaazapentatriacontanedioic acid.

14.6 g (=16 mmoles) of the gadolinium(III) complex thus obtained aresuspended in 200 ml of water and mixed drop by drop with 31.4 ml of 1Nsodium hydroxide solution. After 1 hour, a clear solution is obtained,filtered and then concentrated in vacuo. After drying in vacuo at 80° C.13.2 g (87% of theory) of a white powder, with good aqueous solubilityand a melting point of 279°-285° C., are obtained.

Similarly, di-N-methylglucamine salt of gadolinium(III) complex of13,23-dioxo-15,18,21 -tris (carboxymethyl )-12,15,18,21,24-pentaazapentatriacontanedioic acid, C₅₀ H₉₆ GdN₇ O₂₂ isobtained with N-methyl -glucamine instead of sodium hydroxide solution.

EXAMPLE 3

Production of the disodium salt of gadolinium(III) complex of3,9-bis(1-carboxyethyl)-6-carboxymethyl-3,6,9-triazaundecanedioic acid,C₁₆ H₂₂ GdN₃ O₁₀.2 Na

36.2 g (=0.1 mole) of gadolinium(III) oxide and 84.2 g (=0.2 mole) of3,9-bis(1-carboxyethyl)-6-carboxymethyl-3,6,9-triazaundecanedioic acidare suspended in 250 ml of water and refluxed for 1 hour. The smallamount of insoluble material is filtered off and the solution isconcentrated to dryness in vacuo. The residue is pulverized and dried at60° C. in vacuo. 112.8 g (=98° of theory) of the chelate are obtained aswhite powder.

57.6 g (=0.1 mole) of the chelate are introduced in a solution of 0.1mole of sodium hydroxide in 100 ml of water. The solution is set at a pHof 7.5 by addition of another 0.1 mole of sodium hydroxide powder, thesolution is heated to boiling and ethyl alcohol is added drop by dropuntil permanent clouding. After several hours of stirring in an icebath, the crystallizate is suctioned off, washed with ethyl alcohol anddried in vacuo. The disodium salt is obtained as a white powder inquantitative yield.

EXAMPLE 4

Production of the dimorpholine salt of gadolinium(III) complex of3,9-bis(1-carboxyethyl)-6-carboxymethyl-3,6,9-triazaundecanedioic acid,C₂₄ H₄₂ GdN₅ O₁₂

17.4 g (=0.2 mole) of morpholine are dissolved in 50 ml of water. 42.1 g(=0.1 mole) of3,9-bis(1-carboxyethyl)-6-carboxymethyl-3,6,9-triazaundecanedioic acidand then 18.2 g (=0.05 mole) of gadolinium(III) oxide are added andrefluxed until a clear solution occurs. Then acetone is added drop bydrop by drop until a permanent clouding. After several hours stirring inan ice bath, the crystallizate is suctioned off, washed with acetone anddried in vacuo. Dimorpholine salt is obtained in quantitative amount asa white powder.

EXAMPLE 5

Production of the di-N-Methylglucamine salt of gadolinium(III) complexof diethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₂₈ H₅₄ GdN₅ O₂₀

39.3 g (=100 mmoles) of diethylenetriamine-N,N,N',N",N"-pentaacetic acidare suspended in 200 ml of water and mixed with 19.5 g (=100 mmoles) ofN-methylglucamine. Then 18.12 g (=50 mmoles) of gadolinium(III) oxide,Gd₂ O₃ are added in portions and the resulting suspension is heated to95° C. After about 1 hour, it is mixed with another 19.5 g (=100 mmoles)of N-methylglucamine and, after two more hours of heating, a clearsolution is obtained. After complete reaction (testing with xylenolorange) it is filtered from the small amount of undissolved material andthe filtrate is concentrated in vacuo to dryness. The residue is againdissolved in 100 ml of water and stirred into 256 ml of ethyl alcohol.After several hours of cooling, the crystallizate is suctioned off,washed with cold ethyl alcohol and dried at 60° in vacuo. 92.7 g (99% oftheory) of a white powder with an uncharacteristic melting point isobtained.

Acetone, propyl alcohol or isopropyl alcohol can also be used instead ofethyl alcohol for purifying the complex salt.

Correspondingly, there are obtained:

with dysprosium(III) oxide, Dy₂ O₃ di-N-methylglucamine salt ofdysprosium(III) complex of diethylenetriamine-N,N,N',N",N"-pentaaceticacid, C₂₈ H₅₄ DyN₅ O₂₀ ;

with lanthanum(III) oxide, La₂ O₃ di-N-methylglucamine salt oflanthanum(III) complex of diethylenetriamine-N,N,N',N",N"-pentaaceticacid, C₂₈ H₅₄ LaN₅ O₂₀ ;

with ytterbium(III) oxide, Yb₂ O₃ di-N-methylglucamine salt ofytterbium(III) complex of diethylenetriamine-N,N,N',N",N"-pentaaceticacid, C₂₈ H₅₄ YbN₅ O₂₀

with samarium(Ill) oxide, Sm₂ O₃ di-N-methylglucamine salt of samarium(III) complex of diethylenetriamine-N,N,N',N", N",-pentaacetic acid, C₂₈H₅₄ SmN₅ O₂₀ ;

with holmium(III) oxide, Ho₂ O₃ di-N-methylglucamine salt ofholmium(III) complex of diethylenetriamine-N,N,N',N",N"-pentaaceticacid, C₂₈ H₅₄ HoN₅ O₂₀ ;

with bismuth(III) oxide, Bi₂ O₃ di-N-methylglucamine salt ofbismuth(III) complex of diethylenetriamine-N,N,N',N",N"-pentaacetic acidC₂₈ H₅₄ BiN₅ O₂₀ ;

with gadolinium(III) oxide, Gd₂ O₃ tri-N-methylglucamine salt ofgadolinium(III) complex oftriethylenetetraamine-N,N,N',N",N",N"-hexaacetic acid, C₃₉ H₇₈ Gdn₇ O₂₇;

Further, there are obtained:

with holmium(III) oxide, Ho₂ O₃ and ethanolamine instead ofN-methylglucamine diethanolamine salt of holmium(III) complex ofdiethylenetriamine-1N, N, N', N",N"-pentaacetic acid, C₁₈ H₃₄ HoN₅ O₁₂ ;

with gadolinium(III) oxide, Gd₂ O₃ and lysine instead ofN-methylglucamine dilysine salt of gadolinium(III) complex ofdiethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₂₆ H₄₈ GdN₇ O₁₄.

With the use of diethanolamine the di-diethanolamine salt ofholmium(III) complex of diethylenetriamine-pentaacetic acid, C₂₂ H₄₂HoN₅ O₁₄.

The salts appear as .white powders with an uncharacteristic meltingpoint.

EXAMPLE 6

Production of the disodium salt Of gadolinium(III) complex ofdiethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₁₄ H₁₈ GdN₃ O₁₀.2 Na

18.2 g (=0.05 mole) of gadolinium(III) oxide and 39.3 g (=0.1 mole) ofdiethylenetriaminepentaacetic acid are suspended in 110 ml of water andrefluxed for 1 hour. The clear solution is cooled and brought to pH 7.5by addition of about 80 ml of 5N sodium hydroxide solution. It is againheated to boiling and 250 ml of ethyl alcohol are added drop by drop.After several hours of stirring in an ice bath, the crystallizate issuctioned off, washed with ice-cold ethyl alcohol and dried in vacuo at60° C. A white powder, that does not melt up to 300° C. is obtained inquantitative amount.

In a corresponding way, there are obtained:

with dyprosium(III) oxide, Dy₂ O₃ disodium salt of dyprosium(III)complex of diethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₁₄ H₁₈LaN₃ O₁₀.2 Na;

with lanthanum(III) oxide, La₂ O₃ disodium salt of lanthanum(III)complex of diethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₁₄ H₁₈LaN₃ O₁₀.2 Na;

with holmium(III) oxide, Ho₂ O₃ disodium salt of holmium(III) complex ofdiethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₁₄ H₁₈ HoN₃ O₁₀.2 Na;

with ytterbium(III) oxide, Yb₂ O₃ disodium salt of ytterbium(III)complex of diethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₁₄ H₁₈YbN₃ O₁₀.2 Na;

with samarium(III) oxide, Sm₂ O₃ disodium salt of samarium(III) complexof diethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₁₄ H₁₈ SmN₃ O₁₀.2Na;

with erbium(III) oxide, Eb₂ O₃ disodium salt of erbium(III) complex ofdiethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₁₄ H₁₈ EbN₃ O₁₀.2 Na;

with gadolinium(III) oxide, Gd₂ O₃ sodium salt of digadolinium(III)complex of tetraethylenepentamine-N,N,N',N",N'",N'", N'"-heptaaceticacid, C₂₂ H₃₀ Gd₂ N₅ O₁₄. Na.

These salts appear as white powders with an uncharacteristic meltingpoint and have a very good aqueous solubility.

EXAMPLE 7

Production of the N-methylglucamine salt of iron(III) complex ofdiethylenetriaminepentaacetic acid, C₂₁ H₃₇ FeN₄ O₁₅

35.40 g (=90 mmoles) of diethylenetriaminepentaacetic acid are suspendedin 100 ml of water and mixed with 24.3 g (=90 mmoles) of iron(III)chloride hexahydrate (FeCl₃.6 H₂ O) dissolved in 100 ml of water. Thesuspension, which is dark broom at first, is heated to 95° C., Afterabout 1 hour, the color changes to light yellow. 270 ml of 1N sodiumhydroxide. solution is added to neutralize the resulting hydrochloricacid and it is heated for another 3 hours to 95° C. The resulting lightyellow precipitate is auctioned off, washed with water until free ofchloride and dried in vacuo at 60° C. 17.85 g (45% of theory) of a lightyellow powder, with a melting point of >300° C. is obtained.

17.85 g (=40 mmoles) of the resulting iron(III) complex are suspended in200 ml of water and thoroughly mixed in portions with 7.8 g (=40 mmoles)of N-methylglucamine. It is heated for about 3 hours to 50° C. and anearly clear, reddish brown solution is obtained, which is filtered andthen concentrated in vacuo to dryness. The residue is dried in vacuo at50° C. 24.3 g (95% of theory) of a reddish brown powder with a meltingpoint of 131°-133° C. are obtained.

With sodium hydroxide solution instead of the organic bases, there areobtained:

sodium salt of iron(III) complex of ethylenediaminetetracetic acid, C₁₀H₁₂ FeN₂ O₈. Na

sodium salt of iron(III) complex oftrans-1,2-cyclohexenediaminetetraacetic acid, C₁₄ H₁₈ FeN₂ O₈. Nadisodium of iron(Ill) complex ofdiethylenetrinitrilopenta(methanephosphonic acid), C₉ H₂₃ FeN₃ O₁₅ P₅.2Na

sodium salt of iron(III) complex of1,10-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid, C₁₄ H₂₀ FeN₂ O₁₀.Na

sodium salt of iron(III) complex of ethylenediaminetetraacethydroxamicacid, C₁₀ H₁₆ FeN₆ O₈. Na

In a corresponding way, there are obtained with N-methylglucamine:

di-N-m ethylglucamine salt of iron (III) complex ofdiethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₂₈ H₅₄ FeN₅ O₂₀

N-methylglucamine salt of iron(IlI) complex oftrans-1,2-cyclohexenediamine-N,N,N',N'-tetraacetic acid, C₂₁ H₃₆ FeN₃O₁₃

N-methyleglucamine salt of iron(III) complex ofethylenediamine-N,N,N',N'-tetraacetic acid, C₁₇ H₃₀ FeN₃ O₁₃

tri-N-methylglucamine salt of iron(III) complex oftriethylenetriamine-N,N,N',N",N'", N'"-hexaacetic acid, C₃₉ H₇₈ FeN₇O₃₇.

With the use of diethanolamine instead of N-methylglucamine,di-diethanolamine salt of iron(III) complex ofdiethylenetriamine-N,N,N",N",N"-pentaacetic acid, C₂₂ H₄₂ FeN₅ O₁₄ isobtained.

EXAMPLE 8

Production of the N-methylglucamine salt of gadolinium(III) complex oftrans-1,2-cyclohexenediamine-N,N,N',N'-tetraaetic acid, C₂₁ H₃₆ GdN₃ O₁₃

20.78 g (=60 mmoles) oftrans-1,2-cyclohexenediamine-N,N,N',N'-tetraacetic acid are suspended in150 ml of water. After addition of 11.7 g (=60 mmoles) ofN-methylglucamine, a nearly clear solution is obtained, to which 10.88 g(=30 mmoles) of gadolinium oxide (Gd₂ O₃) are added. The newly resultingsuspension is heated for 6 hours to 95° C. It is filtered off from thesmall amount of undissolved material and the filtrate concentrated todryness. The residue is dried in vacuo at 60° C. and pulverized. 38.6 g(92% of theory) of a white powder with a melting point of 258°-261° C.are obtained.

In a similar way, the sodium salt of gadolinium(III)complex oftrans-1,2-cyclohexenediamine-N,N,N',N'-tetraacetic acid, C₁₄ H₁₈ GdN₂O₈. Na is obtained with sodium hydroxide solution instead ofN-methylglucamine.

The sodium salt of chromium(III) complex ofethytenediamine-N,N,N',N'-tetraacetic acid, C₁₀ H₁₂ CrN₂ O₈. Na isobtained with freshly precipitated chromium(III) hydroxide, Cr(OH)₃.

EXAMPLE 9

Production of the disodium salt of manganese(II) complex oftrans-1,2-cyclohexylenediamine-N,N,N',N'-tetraacetic acid, C₁₄ H₁₈MnN_(O) ₈. 2 Na

34.6 g (=100 mmoles) oftrans-1,2-cyclohexenediamine-N,N,N',N'-tetraacetic acid are suspendedunder nitrogen in 100 ml of water and mixed with 11.5 g (=100 mmoles) ofmanganese(II) carbonate, MnCO₃. It is heated to 95° C. and 200 ml of 1Nsodium hydroxide solution are added drop by drop. The clear solution isconcentrated in vacuo and the residue dried in vacuo at 60° C. 40.8 g(92% of theory) of a pink powder are obtained.

In a corresponding way there are obtained:

from copper(II) carbonate the disodium salt of copper(II) complex oftrans-1,2-cyclohexenediaminetetraacetic acid, C₁₄ H₁₈ CuN₂ O₈. 2 Na;

from cobalt(II) carbonate the disodium salt of cobalt(II) complex oftrans-1,2-cyclohexenediaminetetraacetic acid, C₁₄ H₁₈ CoN₂ O₈. 2 Na;

from nickel(II) carbonate the disodium salt of nickel(II) complex oftrans-1,2-cyclohexenediaminetetraacetic acid, C₁₄ H₁₈ NiN₂ O₈. 2 Na.

With N-methylglucamine instead of sodium hydroxide solution, thefollowing are obtained:

di-N-methylglucamine salt of manganese(II) complex oftrans-1,2-cyclohexenediaminetetraacetic acid, C₂₈ H₅₄ MnN₄ O₁₈ ;

di-N-methylglucamine salt of manganese(II) complex ofdl-2,3-butylenediaminetetraacetic acid, C₂₆ H₅₂ MnN₄ O₁₈ ;

di-N-methylglucamine salt of manganese(II) complex ofethylenediamine-N,N,N',N'-tetraacetic acid, C₂₄ H₄₈ MnN₄ O₁₈ ;

di-N-methylglucamine salt of manganese(II) complex ofdl-1,2-butylenediamine-N,N,N',N'-tetraacetic acid, C₂₆ H₅₂ MnN₄ O₁₈ ;

di-N-methylglucamine salt of manganese(II) complex ofdl-1,2-diaminopropane-N,N,N',N'-tetraacetic acid, C₂₅ H₅₀ MnN₄ O₁₈ ;

tri-N-methylglucamine salt of manganese(II) complex ofdiethylenetriaminepentaacetic acid, C₃₅ H₇₂ MnN₆ O₂₅ ;

with nickel(II) carbonate, NiCO₃ di-N-methlglucamine salt of nickel(II)complex of ethylenediamine-N,N,N',N'-tetraacetic acid, C₂₄ H₃₈ NiN₄ O₁₈;

with cobalt(II) carbonate, CoCO₃ and ethanolamine diethanolamine salt ofcobalt(II) complex of ethylenediamine-N,N,N',N'tetraacetic acid, C₁₄ H₂₈CoN₄ O₁₀ ;

with copper(II) carbonate, CuCO₃, and ethanolamine diethanolamine saltof copper(II) complex of ethylenediamine-N,N,N',N'-tetraacetic acid, C₁₄H₂₈ CuN₄ O₁₀ ;

with manganese(II) carbonate, MnCO₃, and diethanolaminetridiethanolamine salt of manganese(II) complex ofdiethylenetriamine-N,N,N',N",N"-pentaacetic acid, C₂₆ H₅₄ MnN₆ O₁₆ ;

with manganese(II) carbonate, MnCO₃, and morpholine dimorpholine salt ofmanganese(II) complex of ethylenediamine-N,N,N",N"-tetraacetic acid, C₁₈H₃₂ MnN₄ O₁₀.

EXAMPLE 10

N-methylglucamine salt of gadolinium(III) complex ofethylenediamine-N,N,N',N'-tetraacetic acid, C₁₇ H₃₀ GdN₃ O₁₃

29.2 g (=100 moles) of ethylenediamine-N,N,N',N'-tetraacetic acid aresuspended in 100 ml of water and heated to 95° C. with 18.1 g (=50mmoles) of gadolinium(III) oxide. During heating up, 19.5 g (=100mmoles) of N-methylglucamine are added by portions. After about 3 hours,a clear solution is obtained, which is filtered and concentrated invacuo to dryness. The residue is dried in vacuo at 60° C. 61.3 g (95% oftheory) of a white powder with an uncharacteristic melting point areobtained.

In an analogous way, there are obtained:

with dysprosium(III) oxide, Dy₂ O₃ N-methylglucamine salt ofdysprosium(III) complex of ethylenediamine-N,N,N',N'-tetraacetic, H₁₇H₃₀ DyN₃ O₁₃ ; N,N,N',N'-tetraacetic, C₁₇ H₃₀ DyN₃ O₁₃ ;

N-methylglucamine salt of gadolinium(III) complex of1,10-diaza-4,7-dioxadecane-1,1,10,10-tetraacetic acid, C₂₁ H₃₈ GdN₃ O₁₅;

N-methylglucamine salt of gadolinium(III) complex of1,2-diphenylethylenediaminetetraacetic acid, C₂₉ H₃₈ N₃ O₁₃ Gd;

with lead(II) oxide, PbO, and sodium hydrochloride disodium salt oflead(II) complex of ethylenediaminetetraacetic acid, C₁₀ H₁₂ N₂ O₈ Pb. 2Na;

with freshly precipitated chromium(III) hydroxide, Cr(OH)₃. Na sodiumsalt of chromium(III) complex of ethylenediaminetetraacetic acid, C₁₀H₁₂ CrN₂ O₈ ; and analogously

sodium salt of gadolinium(III) complex ofethylenediaminetetraacethydroxamic acid, C₁₀ H₁₆ GdN₆ O₈. Na;

sodium salt of gadolinium(III) complex ofethylenediamine-N,N,N',N'-tetraacetic acid, C₁₀ H₁₂ GdN₂ O₈. Na.

EXAMPLE 11

Production of the sodium salt of gadolinium(III) complex of1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid, C₁₆ H₂₄GdN₄ O₈. Na

4.0 g (=10 mmoles) of1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid aresuspended in 20 ml of water and mixed with 10 ml of 1N sodium hydroxidesolution. 1.8 g (=5 mmoles) of gadolinium(III) oxide, Gd₂ O₃, are addedand the suspension is heated for 2 hours to 50° C. The clear solution isfiltered and concentrated in vacuo. The residue is dried and pulverized.5.5 g (95% of theory) of a white powder are obtained.

In a similar way, there are obtained:

N-methylglucamine salt of gadolinium(III) complex of1,4,7,10-raazacyclododecane-N,N',N",N"'-tetraacetic acid, C₂₃ H₄₂ GdN₅O₁₃

sodium salt of gadolinium(III) complex of1,4,8,11-tetraazacyclotetradecane-N,N',N',N"'-tetraacetic acid, C₁₈ H₂₈GdN₄ O₈. Na.

EXAMPLE 12

Production of the tetra-N-methylglucamine salt of gadolinium(III)complex of ethylenedinitrilo-tetrakis(methanephosphonic acid), C₃₄ H₈₅GdN₆ O₃₂ P₄

9.11 g (=20 mmoles) of ethylenedinitrilo-tetrakis(methanephosphonicacid) are suspended in 150 ml of water and adjusted to a pH of 5 with asuitable amount of N-methylglucamine. 3.6 g (=10 mmoles) ofgadolinium(III) oxide, Gd₂ O₃, are added and heated to 70° C. Afterabout 1 hour a clear solution is obtained, which is mixed with theremaining portion of N-methylglucamine. Altogether, 15.6 g (=80 mmoles)of N-methylglucamine are used. The solution is concentrated in vacuo todryness and the remaining gelatinous residue is added to 200 ml ofacetonitrile. It is stirred at 30° C. for about 20 hours and theresulting fine precipitate is suctioned off. After drying in vacuo at40° C., 234 g (85% of theory) of a white powder with a melting point of115°-118° C. are obtained.

In a similar way, there are obtained:

hepta-N-methylglucamine salt of gadolinium(III) complex ofdiethylenetriamine-N,N,N',N",N"-penta(methanephosphonic acid), C₅₈ H₁₄₄GdN₁₀ O₅₀ P₅

and with the use of sodium hydroxide solution instead ofN-methylglucamine

disodium salt of gadolinium(III) complex ofdiethylenetrinitrilopenta(methanephosphonic acid), C₉ H₂₃ GdN₃ O₁₅ P₅. 2Na

EXAMPLE 13

Production of the disodium salt of manganese(II) complex ofethylenedinitrilotetra(acethydroxamic acid), C₁₀ H₁₆ MnN₆ O₈. 2 Na

2.30 g of manganese(II) carbonate and 7.05 g ofethylenedinitrilotetra(acethydroxamic acid) are refluxed in 18 ml ofwater for 3 hours. Then the pH is adjusted to 7 by addition of dilutesodium hydroxide solution and 40 ml of acetone are added drop by drop.After several hours of stirring in an ice bath, the precipitatedcrystallizate is suctioned off, washed with acetone and dried at 50° C.in vacuo. A dihydrate is obtained in quantitative amount as a whitepowder with a melting point above 300° C.

EXAMPLE 14

Production of a mixed salt solution of sodium and N-methylglucamine saltof gadolinium(III) complex of diethylenetriaminepentaacetic acid

a) Production of the mono-N-methylglucamine salt of the complex, C₂₁ H₃₇GdN₄ O₁₅

195.2 g (1 mole) of N-methylglucamine are dissolved in 7 liters ofwater. Then 393.3 g (1 mole) of diethylenetriaminepentaacetic acid and181.3 g (0.5 mole) of gadolinium oxide, Gd₂ O₃, are added and refluxedfor 2 hours. The filtered clear solution is spray dried. A whitecrystalline powder with a water content of 2.6%, which sinters at 133°C. and melts with foaming at 190° C. is obtained.

b) Production of the neutral mixed salt solution

730.8 g (=1 mole) of the salt obtained under a) are suspended in 630 mlof water p.i. (pro injectione, i.e., sterile) and 40 g (=1 mole) ofsodium hydroxide powder are added in portions. Water p.i. is added tothe neutral solution to make 1000 ml, it is put into bottles through apyrogen filter and sterilized by heat. This one molar solution contains753.8 g of mixed salt per liter.

EXAMPLE 15

Production of a solution of the di-N-methylglucamine salt ofgadolinium(III) complex of diethylenetriaminepentaacetic acid

535.0 g (=730 mmoles) of the salt described in example 5 are made into apaste in 500 ml of water p.i. and brought to solution by addition of142.4 g (=730 mmoles) of N-methylglucamine at pH 7.2. Then water p.i. isadded to make 1000 ml, the solution is put into ampoules and sterilizedby heating.

EXAMPLE 16

Production of a solution of the disodium salt of gadolinium(III) complexof diethylenetriaminepentaacetic acid

485.1 g (=820 mmoles) of the disodium salt obtained in example 6 aremade into a paste in 500 ml of water p.i. Then water p.i. is added tomake 1000 ml, the solution is put into ampoules and sterilized byheating.

EXAMPLE 17

Production of a solution of the disodium salt of gadolinium(III) complexof13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentazapentatriacontanedioicacid

392.0 g (=400 mmoles) of the salt described in example 2 are made into apaste in 500 ml of water p.i. and dissolved by adding water p.i. to make1000 ml with gentle heating. The solution is put into bottles andsterilized by heating.

EXAMPLE 18

Production of a solution of the N-methylglucamine salt ofgadolinium(III) complex of 1,4,7,10-tetraazacyclododecanetetraaceticacid

370.9 g (=500 mmoles) of the salt mentioned in example 11 is made into apaste in 500 ml of water p.i. and dissolved by adding water p.i. to make1000 ml. The solution is put into ampoules and sterilized by heating.

EXAMPLE 19

Production of a solution of the di-N-methylglucamine salt ofmanganese(II) complex of trans-1,2-cyclohexenediaminetetraacetic acid.

395.9 g (=500 mmoles) of the salt mentioned in example 9 are suspendedin 500 ml of water p.i. It is mixed with 1.3 g of ascorbic acid andbrought to solution by adding water p.i. to make 1000 ml. The solutionis sterilized by filtration and put into ampoules.

EXAMPLE 20

Production of a solution of the tri-N-methylglucamine salt ofmanganese(II) complex of diethylenetriaminepentaacetic acid

514.4 g (=500 mmoles) of the salt mentioned in example 9 are suspendedin 600 ml of water p.i. It is mixed with 1.3 g of ascorbic acid anddissolved by adding water p.i. to make 1000 ml. The solution issterilized by filtering and put into ampoules.

EXAMPLE 21

Production of a solution of the di-N-methylglucamine salt of iron(III)complex of diethylenetriaminepentaacetic acid

44.6 g (=0.1 mole) of the iron(III) complex ofdiethylenetriaminepentaacetic acid obtained in example 7 are suspendedin 40 ml of water p.i. After addition of 0.18 g of tromethaminehydrochloride and 39.1 g (=0.2 moles) of N-methylglucamaine it isdissolved to neutrality, water p.i. is added to the solution to bring itto 100 ml, it is put into ampoules and sterilized by heating.

EXAMPLE 22

Production of a solution of the gadolinium(III) complex ofnitrilotriacetic acid

1.9 g (=10 mmoles) of nitrilotriacetic acid and 1.8 g (=5 mmoles) ofgadolinium(III) oxide are dissolved in 100 ml of water p.i. withheating. The solution is put into ampoules and sterilized by heating.

EXAMPLE 23

Production of a solution of the N-methylglucamine salt ofgadolinium(III) complex of ethylenediaminetetraacetic acid.

38.52 g (=60 mmoles) of the substance described in example 10 aredissolved in 70 ml of water p.i. After addition of 0.12 g of water p.i.is added to make 100 ml, the solution is put into ampoules andsterilized by heating.

EXAMPLE 24

Production of a solution of the di-N-methylglucamine salt ofdysprosium(III) complex of diethylenetriaminepentaacetic acid

35.7 g (=60 mmoles) of the dysprosium(III) complex ofdiethylenetriaminepentaacetic acid (8.0% water content) are suspended in70 ml of water p.i. and brought to solution by addition of 21.2 g (=120mmoles) of N-methylglucamaine at a pH of 7.5 Then water p.i. is added tomake 100 ml, the solution is put into ampoules and sterilized byheating.

EXAMPLE 25

Production of a solution of the N-methylglucamine salt ofgadolinium(III) complex of trans-1,2-cyclohexenediaminetetraacetic acid

555.8 g (=0.8 mole) of the salt described in example 8 are dissolved inwater p.i. to make 1000 ml. After filtration through a pyrogen filter,the solution is put into ampoules and sterilized by heating.

EXAMPLE 26

Production of a solution of the N-methylglucamine salt of ruthenium(III)complex of 1,10-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid

15.6 g (=0.03 mole) of the ruthenium(III) complex 6f1,10-diaza-4,7-dithiadecane-1,1,10,10-tetraacetic acid are suspended in50 ml of water p.i. and brought to solution at pH 7.5 by addition of 5.9g (=0.03 moles). of N-methylglucamine. Water p.i. is added to make 1000ml, the solution is put into ampoules and sterilized by heating.

EXAMPLE 27

Production of a solution of the dilysine salt of gadolinium(III) complexof diethylenetriaminepentaacetic acid

273.8 g (=0.5 mole) of the gadolinium(III) complex ofdiethylenetriaminepentaacetic acid are suspended in 500 ml of water p.i.292.4 g (=1 mole) of lysine are added, left to stir for several hourswith gentle heating and then water p.i. is added to make 1000 ml. Thesolution is put in bottles and sterilized by heating.

EXAMPLE 28

Production of a solution of the tri-N-methylglucamine salt of molybdenum(VI) complex of diethyelenetriaminepentaacetic acid

18.8 g (=0.28 mole) of the complex H₃ [Mo₂ O₂ (OH)₄. C₁₄ H₂₃ N₃ O₁₂₀ ]are suspended in 50 ml of water p.i. and dissolved to neutrality byaddition of 16.4 g (=0.84 mole) of N-methylglucamine. 0.15 g oftromethamine is added, water p.i. is added to make 100 ml, the solutionis subjected to sterilization by filtering and put into ampoules.

EXAMPLE 29

Production of a solution of the disodium salt of manganese(II) complexof ethylenediaminetetraacetic acid

343.2. g (=1 mole) of the manganese(II) complex ofethylenediamtnetetraacetic acid are suspended in 500 ml of water p.i.and dissolved to neutrality by addition by portions of 80 g (=2 moles)of sodium hydroxide. After addition of 1.5 g of tromethamine, water p.i.is added to the solution to make 1000 ml, it is put into bottles andsterilized by heating.

EXAMPLE 30

Production of a solution of the sodium salt of iron(III) complex ofethylenediaminetetraacetic acid

345.7 g (=1 mole) of the iron(III) complex of ethylenediaminetetraaceticacid are suspended in 500 ml of water p.i. and dissolved to neutralityby addition by portions of 40 g (=1 mole) of sodium hydroxide. Afteraddition of 1.5 g of tromethamine, water p.i. is added to the solutionto make 1000 ml, it is put in bottles and sterilized by heating.

EXAMPLE 31

Production of a solution of the disodium salt of iron(III) complex ofdiethylenetriaminepentaacetic acid

334.6 g (=0.75 mole) of the iron(III) complex ofdiethylenetriaminepentaacetic acid are suspended in 500 ml of water p.i.and dissolved to neutrality by addition by portions of 60 g (=1.5 moles)of sodium hydroxide. Water p.i. is added to the solution to make 1000ml, it is put into bottles and sterilized by heating.

EXAMPLE 32

Production of a solution of the sodium salt of gadolinium(III) complexof trans-1,2-cyclohexenediaminetetraacetic acid

558.6 (=1 mole) of the salt mentioned in example 8 are dissolved inwater p.i. to 1000 ml. The solution is put into bottles and sterilizedby heating.

EXAMPLE 33

Production of a solution of the N-methylglucamaine salt ofgadolinium(III) complex of 1,2-diphenylethylenediaminetetraacetic acid

396.9 g (=500 mmoles) of the salt described in example 10 are made intoa paste in 600 ml of water p.i. and dissolved by addition of water tomake 1000 ml. The solution is put into ampoules and sterilized byheating.

EXAMPLE 34

Production of a solution of the sodium salt of iron(III) complex ofethylenediaminetetraacetic acid

183.5 g (=500 mmoles) of the salt mentioned in example 7 are made into apaste in 500 ml of water p.i. 1.0 g of tromethamine is added, water p.i.is added to make 1000 ml, the solution is put into ampoules andsterilized by heating.

EXAMPLE 35

Production of a solution of the di-N-methylglucamine salt oflanthanum(III) complex of diethylenetriaminepentaacetic acid

459.8 g (=500 mmoles) of the salt mentioned in example 5 are made into apaste in 650 ml of water p.i. and brought to solution by addition ofwater p.i. to make 1000 ml. The solution is put into ampoules andsterilized by heating.

EXAMPLE 36

Production of a solution of the di-N-methylglucamine salt ofbismuth(III) complex of diethylenetriaminepentaacetic acid

692.8 g (=700 mmoles) of the salt mentioned in example 5 are made into apaste in 600 ml of water p.i. and after addition of 1.8 g oftromethamine dissolved by addition of water p.i. to make 1000 ml withgentle heating. The solution is put into ampoules and sterilized byheating.

EXAMPLE 37

Production of a solution of the di-N-methylglucamine salt ofholmium(III) complex of diethylenetriaminepentaacetic acid

662.0 g (=700 mmoles) of the salt mentioned in example 5 are made into apaste in 600 ml of water p.i. and after addition of 1.8 g oftromethamine, are dissolved by addition of water p.i. to make 1000 mlWith gentle heating. The solution is put into ampoules and sterilized byheating.

EXAMPLE 38

Production of a solution of the di-N-methylglucamine salt ofytterbium(III) complex of diethylenetriaminepentaacetic acid

476.9 g (=500 mmoles) of the salt mentioned in example 5 are made into apaste in 650 ml of water p.i. and after addition of 1.5.g oftromethamine dissolved by addition of water p.i. to make 1000 ml. Thesolution is put into ampoules and sterilized by heating.

EXAMPLE 39

Production of a solution of the disodium salt of lanthanum(III) complexof diethylenetriaminepentaacetic acid

573.2 g (=1000 mmoles) of the salt mentioned in example 6 are made intoa paste in 650 ml of water p.i. and dissolved by addition of water p.i.to make 1000 ml. The solution is put into ampoules and sterilized byheating.

EXAMPLE 40

Production of a solution of the disodium salt of dysprosium(III) complexof diethylenetriaminepentaacetic acid.

477.4 g (=800 mmoles) of the salt mentioned in example 6 are made into apaste in 600 ml of water p.i. and dissolved by addition of water p.i. tomake 1000 ml. The solution is put into ampoules and sterilized byheating.

EXAMPLE 41

Production of a solution of the disodium salt of holmium(III) complex ofdiethylenetriaminepentaacetic acid

299.6 g (=500 mmoles) of the salt mentioned in example 6 are made into apaste in 500 ml of water p.i. and dissolved by addition of water p.i. tomake 1000 ml. The solution is put into ampoules and sterilized byheating.

EXAMPLE 42

Production of a solution of the disodium salt of ytterbium(III) complexof diethylenetriaminepentaacetic acid.

303.5 g (=500 mmoles) of the salt mentioned in example 6 are made into apaste in 500 ml of water p.i. and dissolved by addition of water p.i. tomake 1000 ml. The solution is put into ampoules and sterilized byheating.

EXAMPLE 43

Production of a solution of the tetra-N-methylglucamine salt ofgadolinium(III) complex of ethylenedinitrilo-tetrakis(methanephosphonicacid)

137.1 g (=100 mmoles) of the salt mentioned in example 1.2. are madeinto a paste in 500 ml of water p.i. and after addition of 0.8 g oftromethamine are dissolved by addition of water p.i. to make 1000 ml.The solution is put into ampoules and sterilized by heating.

EXAMPLE 44

Production of a solution of gadolinium(III) complex ofN'-(2-hydroxyethyl)ethylenediamine-N,N,N'-triacetic acid

1.9 g (=6.7 mmoles) ofN'-(2-hydroxyethyl)ethylenediamine-N,N,N'-triacetic acid and 1.2 g(=3.35 moles) of gadolinium(III) oxide are dissolved in 6 ml of waterp.i. with heating. The solution is put into ampoules and sterilized byheating.

EXAMPLE 45

Production of a solution of the disodium salt of manganese(II) complexof trans-1,2-cyclohexenediaminetetraacetic acid

44.3 g (=100 mmoles) of the salt mentioned in example 9 are made into apaste under nitrogen cover in 60 ml of water p.i. and brought tosolution by addition of water p.i. to make 100 ml. The solution is putinto ampoules and sterilized by heating.

EXAMPLE 6

Production of a solution of the sodium salt of gadolinium(III) complexof 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid

552.6 g (=1 mole) of the salt mentioned in example 11 are dissolved inwater p.i. to make 1000 ml. The solution is put into bottles andsterilized by heating.

EXAMPLE 47

Production of a solution of the disodium salt of bismuth(III) complex ofdiethylenetriaminepentaacetic acid.

23.4 g (=50 mmoles) of bismuth(III) oxide are suspended in 50 ml ofwater p.i. After addition of 39.3 g (=100 mmoles) ofdiethylenetriaminepentaacetic acid and 4.0 g (=50 mmoles) of sodiumhydroxide, it is refluxed to a clear solution. The solution, cooled toroom temperature, is neutralized by addition of 4.0 g of sodiumhydroxide and water p.i. is added to make 100 ml. The solution is putinto ampoules and sterilized by heating.

EXAMPLE 48

Production of a solution of the disodium salt of samarium(III)complex ofdiethylenetriaminepentaacetic acid

58.5 g (=100 mmoles) of the salt mentioned in example 6 are dissolved in65 ml of water p.i. with heating. Water p.i. is added to make a totalvolume of 100 ml, it is put into ampoules and sterilized by heating.

EXAMPLE 49

Production of a solution of the di-N-methylglucamine salt ofgadolinium(III) complex of13,23-dioxo-15,18,21-tris(carboxymethyl)-12,15,18,21,24-pentaazapentatriacontanedioicacid

130.4 g (=100 mmoles) of the salt mentioned in example 2 are made into apaste in 250 ml of water p.i. and dissolved with heating. Water p.i. isadded to make 500 ml, the solution is put into ampoules and sterilizedby heating.

EXAMPLE 50

Production of s solution of the di-N-methylglucamine salt ofmanganese(II) complex of ethylenediaminetetraacetic acid

3.68 g (=5 mmoles) of the substance described in example 9 are dissolvedin 70 ml of water p.i. and the solution is mixed with 0.4 g of sodiumchloride. Then water p.i. is added to make 100 ml and the solution isput into ampoules through a sterilizing filter. The solutions isisotonic with the blood with 280 mOsm.

EXAMPLE 51

Production of a solution of the disodium salt of gadolinium(III)complexof diethylenetrinitrilopenta(methanephosphonic acid)

38.57 g (=50 mmoles) of the substance described in example. 12 are madeinto a paste in 50 ml of water p.i. The pH is adjusted to 7.2 .byaddition of sodium hydroxide powder, and water p.i. is added to make 100ml. The solution is put into ampoules and sterilized by heating.

EXAMPLE 52

Production of a solution of the trisodium salt of manganese(II) complexof diethylenetriaminepentaacetic acid.

39.3 g (=100 mmoles) of diethylenetriaminepentaacetic acid are suspendedin 100 ml of water p.i. under nitrogen and mixed with 11.5 g ofmanganese(II) carbonate. It is heated to 95° C. and 300 ml of 1N sodiumhydroxide solution are added drop by drop. The neutral solution issterilized by filtering and put into ampoules.

EXAMPLE 53

Composition of a powder for protection of a suspension

    ______________________________________                                        4.000 g                                                                             gadolinium (III) complex of diethylenetriaminepentaacetic acid                (water content 8.0%)                                                    3.895 g                                                                             saccharose                                                              0.100 g                                                                             polyoxyethylenepolyoxypropylene polymer                                 0.005 g                                                                             aromatics                                                               8.000 g                                                                       ______________________________________                                    

EXAMPLE 54

Production of a solution of the gadolinium(III) complex of the conjugateof diethylenetriaminepentaacetic acid with human serum albumin

10 m g of 1,5-bis(2,6-dioxomorpholino) -3-azapentane-3-acetic acid areadded to 20 ml of a solution of 3 mg of protein in 0.05 molar sodiumbicarbonate buffer (pH 7-8). It is allowed to stir for 30 minutes atroom temperature and then dialyzed against a 0.3 molar sodium phosphatebuffer. Then 50 mg of gadolium(III) acetate are added and purified bygel chromotography in a Sephadex G25 column. The resulting fraction issterilized by filtering and put into Multivials. A storable dry productis obtained by freeze-drying.

The solution of the corresponding complex conjugate is obtained in asimilar way with immunoglobulin.

EXAMPLE 55

Production of a solution of the gadolium(III) complex of the conjugateof diethylenetriaminepentaacetic acid (DTPA) with monoclonal antibodies

1 mg of a mixed DTPA-anhydride (obtained, for example, from DTPA andisobutyl chloroformate) is added to 20 μl of a solution of 0.3 mg ofmonoclonal antibodies in 0.05 molar sodium bicarbonate buffer (pH 7-8)and stirred for 30 minutes at room temperature. It is dialyzed against0.3 molar sodium phosphate buffer and the resulting antibody fraction ismixed with 2 mg of the gadolinium(III) complex ofethylenediaminetetraacetic acid (EDTA). After purification by gelchromatography with Sephadex G25, the solution sterilized by filteringis put in Multivials and freeze-dried.

A solution of the corresponding gadolinium(III) complex ofCDTA-antibodies is obtained in a similar way by using the mixedanhydride of trans-1,2-diaminocyclohexanetetraacetic acid (CDTA).

The manganese(II) complex of the antibodies coupled with DTPA or CDTA isobtained in a similar way by using the manganese(II) complex ofethylenediaminetetraacetic acid.

EXAMPLE 56

Production of a solution of the gadolinium(III) complex of the conjugateof 1-phenylethylenediaminetetraacetic acid with immunoglobulin

By following the method described in J. Med. Chem. 1974, Vol. 17, p1307, a 2% solution of protein in a 0.12 molar sodium bicarbonatesolution, which contains 0.01 mole of ethylenediaminetetraacetic acid iscooled to +4° C. and mixed drop by drop with the protein equivalentportion of a freshly produced ice-cold diazonium salt solution of1-(p-aminophenyl) -ethylenediaminetetraacetic acid. It is allowed tostir overnight at +4° C. (pH 8.1) and then dialyzed against a 0.1 molarsodium citrate solution. After completion of the dialysis, the solutionof the conjugate is mixed with an excess of gadolinium(III) chloride andultrafiltered to remove ions. Then the solution sterilized by filteringis put into Multivials and freeze-dried.

EXAMPLE 57

Production of a colloidal dispersion of an Mn-CDTA-lipid conjugate

0.1 mmole of distearoylphosphatidylethanolamine and 0.1 mmole ofbisanhydride of trans-1,2-diaminocyclohexanetetraacetic acid are stirredin 50 ml of water for 24 hours at room temperature. 0.1 mmole ofmanganese(II) carbonate is added and restirred for 6 hours at roomtemperature. After purification with a Sephadex G50 column, the solutionsterilized by filtering is put into multivials and freeze-dried.

A colloidal dispersion of the gadolinium-DTPA-lipid conjugate can beobtained in a similar way with gadolinium(III) oxide.

EXAMPLE 58

Production of liposomes loaded with gadolinium-DTPA

By following the method described in Proc. Natl. Acad. Sci. U.S.A. 75,4194, a lipid mixture is produced from 75 mole % of eggphosphatidylcholine and 25 mole % of cholesterol as a dry substance. 500mg of it are dissolved in 30 ml of diethylether and mixed drop by dropin an ultrasonic bath with 3 ml of a 0.1 molar solution of thedi-N-methyglucamine salt of gadolinium(III) complex ofdiethylenetriaminepentaacetic acid in water p.i. After completreaddition of the solution, the treatment with ultrasonic waves iscontinued for 10 more minutes and then concentrated in the Rotavapor.The gelatinous residue is suspended in 0.125 molar sodium chloridesolution and is freed of the unencapsulated contrast medium portions byrepeated centrifuging (20000 g/20 minutes) at 0° C. Finally, theresulting liposomes are freeze-dried in the Multivial. Application is asa colloidal dispersion in 0.9 percent by weight of sodium chloridesolution.

EXAMPLE 59

Production of a solution of the gadolinium(III) complex of the conjugateof 1,4,7-10-tetraazacyclododecanetetracetic acid (DOTA) with monoclonalantibodies

1 mg of a mixed DOTA-anhydride (obtained, for example, from DOTA andisobutyl chloroformate) is added to 20 ul of a solution of 0.3 mg ofmonoclonal antibodies in 0.05 molar sodium bicarbonate buffer (pH 7-8)and stirred for 30 minutes at room temperature. It is dialyzed against0.3 molar sodium phosphate buffer and the resulting antibody fraction ismixed with 2 mg of the gadolinium(III) complex ofethylenediaminetetraacetic acid (EDTA). After purification by gelchromatography with Sephadex G25, the solution sterilized by filteringis put in Multivials and freeze-dried.

The manganese(II) complex of the antibodies coupled with DOTA isobtained is a similar way by using the manganese(II) complex ofethylenediaminetetraacetic acid.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A method of performing an NMR diagnosticprocedure comprising administering to a patient an effective amount ofan NMR diagnostic medium and them exposing the patient to an NMRmeasurement step to which the diagnostic medium is responsive, therebyimaging at least a portion of the patient's body, wherein the diagnosticmedium comprises a physiologically compatible chelate complex of (a) acomplexing agent and (b) at least one central paramagnetic ion of anelement with an atomic number of 21 to 29, 42, 44 or 58 to 70 chelatedtherewith, wherein the complexing agent is of the formula ##STR13##wherein X is --COOY;Y is a hydrogen atom, a metal ion equivalent or aphysiologically compatible cation of an inorganic or organic base oramino acid; and w is a number 1, 2 or 3; provided that at least two ofthe substituents Y are metal ion equivalents of an element with anatomic number of 21 to 29, 42, 44 or 58 to
 83. 2. A method of claim 1wherein the concentration of chelate complex in the medium is 1 μmole to1 mole.
 3. A method of claim 1 wherein the concentration of chelatecomplex in the medium is 1 μmole to 5 mmole.
 4. A method of claim 1wherein the concentration of chelate complex in the medium is 250 mmoleto 1 mole.
 5. A method of claim 1 wherein the chelate complex is derivedfrom a chelating agent which is1,4,7,10-tetraazacyclododecanetetraacetic acid.
 6. A method of claim 1wherein the chelate complex is derived from a chelating agent which is1,4,8,11-tetraazacyclotetradecanetetraacetic acid.
 7. A method of claim1 wherein said paramagneticion is Gd(III).
 8. A method of claim 5,wherein the ion is Gd(III).
 9. A method of claim 8, wherein theremaining Y is lysine, arginine or ornithine.
 10. A method of claim 9,wherein the chelate complex is the lysine salt of the Gd(III) complex of1,4,7,10-tetraazacyclododecanetetraacetic acid.
 11. A method accordingto claim 1, wherein one or two of said Y groups are each aphysiologically compatible cation of an inorganic or organic base oramino acid.
 12. A method according to claim 1, wherein said chelatecomplex is dissolved or suspended in an aqueous medium.
 13. A methodaccording to claim 1, wherein said chelate complex is administeredintravascularly or orally.
 14. A method of performing an NMR diagnosticprocedure comprising administering to a patient an effective amount ofan NMR diagnostic medium and then exposing the patient to an NMRmeasurement step to which the diagnostic medium is responsive, therebyimaging at least a portion of the patient's body, wherein the diagnosticmedium comprises a physiologically compatible chelate complex of (a) acomplexing agent and (b) at least one central paramagnetic ion of anelement with an atomic number of 21 to 29, 42, 44 or 57-70 chelatedtherewith, wherein the complexing agent is of the formula ##STR14##wherein R⁹ is carboxymethyl;A is a hydrocarbon radical; X is N; D is##STR15## R is carboxymethyl; and s and t are, in each case,independently, 0-5; and wherein said complex is optionally a complexwith an inorganic or organic acid.
 15. A method according to claim 14,whereinA is ethylene; s is 0; and t is
 0. 16. A method according toclaim 14, wherein said complexing agent is1,4,8,11-tetraazacyclotetradecane-N,N',N", N'"-tetraacetic acid.
 17. Amethod of performing an NMR diagnostic procedure comprisingadministering to a patient an effective amount of an NMR diagnosticmedium and them exposing the patient to an NMR measurement step to whichthe diagnostic medium is responsive, thereby imaging at least a portionof the patient's body, wherein the diagnostic medium comprises aphysiologically compatible chelate complex of (a) a complexing agent and(b) at least one central paramagnetic ion of an element with an atomicnumber of 21 to 29, 42, 44 or 58 to 70 chelated therewith, wherein thecomplexing agent is of the formula ##STR16## wherein X is --PO₃ HY;Y isa hydrogen atom, a metal ion equivalent or a physiologically compatiblecation of an inorganic or organic base or amino acid; and w is a number1, 2 or 3; provided that at least two of the substituents Y are metalion equivalents of an element with an atomic number of 21 to 29, 42, 44or 58 to
 83. 18. A method according to claim 17, wherein the chelatecomplex further comprises at least one physiologically compatible cationof an inorganic or organic base or amino acid.
 19. A method according toclaim 17, wherein said chelate complex is dissolved or suspended in anaqueous medium.
 20. A method according to claim 17, wherein said chelatecomplex is administered intravascularly or orally.
 21. A method of claim17, wherein the concentration of chelate complex in the medium is 1μmole to 1 mole.
 22. A method of claim 17, wherein the concentration ofchelate complex in the medium is 1 μmole to 5 mmole.
 23. A method ofclaim 17, wherein the concentration of chelate complex in the medium is250 mmole to 1 mole.
 24. A method of claim 17, wherein saidparamagneticion is Gd(III).
 25. A method of performing an NMR diagnosticprocedure comprising administering to a patient an effective amount ofan NMR diagnostic medium and them exposing the patient to an NMRmeasurement step to which the diagnostic medium is responsive, therebyimaging at least a portion of the patient's body, wherein the diagnosticmedium comprises a physiologically compatible chelate complex of (a) acomplexing agent and (b) at least one central paramagnetic ion of anelement with an atomic number of 21 to 29, 42, 44 or 58 to 70 chelatedtherewith, wherein the complexing agent is of the formula ##STR17##wherein X is --CONHOY;Y is a hydrogen atom, a metal ion equivalent or aphysiologically compatible cation of an inorganic or organic base oramino acid; and w is a number 1, 2 or 3; provided that at least two ofthe substituents Y are metal ion equivalents of an element with anatomic number of 21 to 29, 42, 44 or 58 to
 83. 26. A method according toclaim 25, wherein the chelate complex further comprises at least onephysiologically compatible cation of an inorganic or organic base oramino acid.
 27. A method according to claim 25, wherein said chelatecomplex is dissolved or suspended in an aqueous medium.
 28. A methodaccording to claim 25, wherein said chelate complex is administeredintravascularly or orally.
 29. A method of claim 25, wherein theconcentration of chelate complex in the medium is 1 μmole to 1 mole. 30.A method of claim 25, wherein the concentration of chelate complex inthe medium is 1 μmole to 5 mmole.
 31. A method of claim 25, wherein theconcentration of chelate complex in the medium is 250 mmole to 1 mole.32. A method of claim 25, wherein said paramagnetic is Gd(III).
 33. Amethod according to claim 1, wherein said paramagnetic ion ischromium(III), manganese(II), iron(III), iron(II), cobalt(II),nickel(II), copper(II), praseodymium(III), neodymium(III),samarium(III), ytterbium(III), gadolinium(III), terbium(III),dysprosium(III), holmium(III) or erbium(III).
 34. A method according toclaim 5, wherein said paramagnetic ion is chromium(III), manganese(II),iron(III) , iron(II) , cobalt (II) , nickel (II) , copper(II) ,praseodymium(III) , neodymium(III), samarium(III) , ytterbium(III) ,gadolinium(III) , terbium(III) , dysprosium(III), holmium(III) orerbium(III).
 35. A method according to claim 33, wherein saidparamagnetic ion is manganese(II), iron(III), dysprosium(III), orytterbium(III).
 36. A method according to claim 34, wherein saidparamagnetic ion is manganese(II), iron(III), dysprosium(III), orytterbium(III).
 37. A method according to claim 11, wherein saidphysiologically compatible cations are in each case sodium orN-methylglucamine.
 38. A method according to claim 33, wherein one ortwo of said Y groups are each a physiologically compatible cation of aninorganic or organic base or amino acid.
 39. A method according to claim34, wherein one or two of said Y groups are each a physiologicallycompatible cation of an inorganic or organic base or amino acid.
 40. Amethod according to claim 35, wherein one or two of said Y groups areeach a physiologically compatible cation of an inorganic or organic baseor amino acid.
 41. A method according to claim 36, wherein one or two ofsaid Y groups are each a physiologically compatible cation of aninorganic or organic base or amino acid.
 42. A method according to claim37, wherein said physiologically compatible cations are in each casesodium or N-methylglucamine.
 43. A method according to claim 41, whereinsaid physiologically compatible cations are sodium or N-methylglucamine.44. A method according to claim 43, wherein said paramagnetic ion isdysprosium(III).
 45. A method according to claim 43, wherein saidparamagnetic ion is ytterbium(III).
 46. A method according to claim 43,wherein said paramagnetic ion is manganese(II).
 47. A method accordingto claim 36, wherein said paramagnetic ion is iron(III). .
 48. A methodaccording to claim 44, wherein the physiologically compatible cation issodium.
 49. A method according to claim 45, wherein the physiologicallycompatible cation is sodium.
 50. A method according to claim 46, whereinthe physiologically compatible cations are N-methylglucamine.
 51. A NMRcontrast enhancing composition comprising:a chelate complex of Gd withDOTA; and a physiologically acceptable carrier,wherein said compositionis in sterile form.
 52. A NMR contrast enhancing composition comprisinga physiologically compatible chelate complex of (a) a complexing agentand (b) Gd chelated therewith, wherein the complexing agent is of theformula ##STR18## wherein R⁹ is carboxymethyl;A is, in each case,ethylene or propylene; X is N; D is ##STR19## R is carboxymethyl; and sand t are each 0; and a pharmaceutically acceptable carrier, whereinsaid composition is in sterile form.
 53. A composition according toclaim 52, wherein w is each case is
 1. 54. A composition according toclaim 52, wherein said complexing agent is1,4,8,11-tetraazacyclotetra-decane-N,N',N",N"'-tetraacetic acid, saidcomposition being in sterile form.